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Depressive Disorders

Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression.

August 1, 2019 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , ,

Pérez‐Esparza, R., Kobayashi‐Romero, L. F., García‐Mendoza, A. M., Lamas‐Aguilar, R. M., & Fonseca‐Perezamador, A. (2019). Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression. Acta Psychiatrica Scandinavica, 140(2), 182-183., https://doi.org/10.1111/acps.13063
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Classical psychedelics for the treatment of depression and anxiety: A systematic review.

July 30, 2019 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , ,

Abstract

BACKGROUND:
Depression and anxiety are prevalent psychiatric disorders that carry significant morbidity. Pharmacological and psychosocial interventions are used to manage these conditions, but their efficacy is limited. Recent interest into the use of psychedelic-assisted therapy using ayahuasca, psilocybin or lysergic acid diethylamide (LSD) may be a promising alternative for patients unresponsive to traditional treatments. This review aims to determine the efficacy and tolerability of psychedelics in the management of resistant depression.
METHODS:
Clinical trials investigating psychedelics in patients with depression and/or anxiety were searched via MEDLINE, EMBASE and PsychINFO. Efficacy was assessed by measuring symptom improvement from baseline, and tolerability was evaluated by noting the incidence and type of adverse effects reported. Risk of bias was assessed.
RESULTS:
Seven studies, with 130 patients, were analysed in this review. Three were conducted in patients with depression, two in patients with anxiety and two in patients with both. In a supportive setting, ayahuasca, psilocybin, and LSD consistently produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. Psychedelics were well-tolerated. The most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure.
LIMITATIONS:
At present, the number of studies on this subject is very limited; and the number of participating patients within these is also limited as the treatment under investigations is a relatively novel concept.
CONCLUSIONS:
Though further evidence is required, psychedelics appear to be effective in significantly reducing symptoms of depression and anxiety and are well-tolerated.

Muttoni, S., Ardissino, M., & John, C. (2019). Classical psychedelics for the treatment of depression and anxiety: a systematic review. Journal of affective disorders., https://doi.org/10.1016/j.jad.2019.07.076
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Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder

January 27, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , , , , , , ,

Abstract

Background: The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity.

Methods: The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery-Åsberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine.

Results: Montgomery-Åsberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10-11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation.

Conclusions: This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine.

Sumner, R. L., McMillan, R., Spriggs, M. J., Campbell, D., Malpas, G., Maxwell, E., Deng, C., Hay, J., Ponton, R., Kirk, I. J., Sundram, F., & Muthukumaraswamy, S. D. (2020). Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder. Biological psychiatry. Cognitive neuroscience and neuroimaging, 5(1), 45–55. https://doi.org/10.1016/j.bpsc.2019.07.002

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Esketamine for treatment resistant depression.

July 16, 2019 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Areas covered: This review will briefly discuss current treatment options for TRD, then review esketamine. Relevant literature was identified through online database searches, and clinical trial data were provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, then clinical data regarding efficacy and safety for esketamine from Phase 2-3 trials are reviewed. Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician, and social factors that will influence the use of esketamine. While the efficacy of esketamine compared to off-label use of racemic ketamine remains unclear, both esketamine’s approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, although factors such as cost and monitoring requirements may limit its use. While questions remain regarding duration and frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering new hope for TRD.
Swainson, J., Thomas, R. K., Archer, S., Chrenek, C., MacKay, M. A., Baker, G., … & Demas, M. L. (2019). Esketamine for treatment resistant depression. Expert review of neurotherapeutics, 1-13., https://doi.org/10.1080/14737175.2019.1640604
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Psychedelic microdosing benefits and challenges: an empirical codebook.

July 10, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:
Microdosing psychedelics is the practice of consuming very low, sub-hallucinogenic doses of a psychedelic substance, such as lysergic acid diethylamide (LSD) or psilocybin-containing mushrooms. According to media reports, microdosing has grown in popularity, yet the scientific literature contains minimal research on this practice. There has been limited reporting on adverse events associated with microdosing, and the experiences of microdosers in community samples have not been categorized.
METHODS:
In the present study, we develop a codebook of microdosing benefits and challenges (MDBC) based on the qualitative reports of a real-world sample of 278 microdosers.
RESULTS:
We describe novel findings, both in terms of beneficial outcomes, such as improved mood (26.6%) and focus (14.8%), and in terms of challenging outcomes, such as physiological discomfort (18.0%) and increased anxiety (6.7%). We also show parallels between benefits and drawbacks and discuss the implications of these results. We probe for substance-dependent differences, finding that psilocybin-only users report the benefits of microdosing were more important than other users report.
CONCLUSIONS:
These mixed-methods results help summarize and frame the experiences reported by an active microdosing community as high-potential avenues for future scientific research. The MDBC taxonomy reported here informs future research, leveraging participant reports to distil the highest-potential intervention targets so research funding can be efficiently allocated. Microdosing research complements the full-dose literature as clinical treatments are developed and neuropharmacological mechanisms are sought. This framework aims to inform researchers and clinicians as experimental microdosing research begins in earnest in the years to come.
Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L. A., … & Hapke, E. (2019). Psychedelic microdosing benefits and challenges: an empirical codebook. Harm reduction journal, 16(1), 43., https://doi.org/10.1186/s12954-019-0308-4
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Harnessing Neuroimaging to Enhance Our Understanding of the Effects of Ketamine in Depression.

July 1, 2019 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / ,

Jaworska, N., & Phillips, J. L. (2019). Harnessing Neuroimaging to Enhance Our Understanding of the Effects of Ketamine in Depression. Biological psychiatry. Cognitive neuroscience and neuroimaging, 4(7), 603., https://doi.org/10.1016/j.bpsc.2019.05.005
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Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective.

June 19, 2019 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one-third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment-resistant patients with MDD or BD. Accumulating evidence suggests that the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Because (S)-ketamine has higher affinity for NMDAR than (R)-ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)-ketamine exerts greater potency and longer-lasting antidepressant effects than (S)-ketamine in animal models of depression and that (R)-ketamine has less detrimental side-effects than (R,S)-ketamine or (S)-ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid-acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low-voltage-sensitive T-type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ-aminobutyric acid, and type A [GABAA ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed
Hashimoto, K. (2019). Rapid‐acting Antidepressant Ketamine, Its Metabolites and Other Candidates: A Historical Overview and Future Perspective. Psychiatry and Clinical Neurosciences., https://doi.org/10.1111/pcn.12902
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Interaction of Sex and Age on the Dissociative Effects of Ketamine Action in Young Healthy Participants.

June 18, 2019 / Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , ,

Abstract

Ketamine is a drug that reduces depressive and elicits schizophrenia-like symptoms in humans. However, it is largely unexplored whether women and men differ with respect to ketamine-action and whether age contributes to drug-effects. In this study we assessed dissociative symptoms via the Clinician Administered Dissociative States Scale (CADSS) in a total of 69 healthy subjects aged between 18 and 30 years (early adulthood) after ketamine or placebo infusion. Dissociative symptoms were generally increased only in the ketamine group post-infusion. Specifically, within the ketamine group, men reported significantly more depersonalization and amnestic symptoms than women. Furthermore, with rising age only men were less affected overall with respect to dissociative symptoms. This suggests a sex-specific protective effect of higher age which may be due to delayed brain maturation in men compared to women. We conclude that it is crucial to include sex and age in studies of drug effects in general and of ketamine-action in specific to tailor more efficient psychiatric treatments. Clinical Trial Registration: EU Clinical Trials Register (EudraCT), trial number: 2010-023414-31.
Derntl, B., Hornung, J., Sen, Z. D., Colic, L., Li, M., & Walter, M. (2019). Interaction of sex and age on the dissociative effects of ketamine action in young healthy participants. Frontiers in neuroscience, 13, https://doi.org/10.3389/fnins.2019.00616
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Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial.

June 4, 2019 / Ayahuasca, Depressive Disorders, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have suggested that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood. Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo. In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms. This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at http://clinicaltrials.gov (NCT02914769).

Almeida, R. N., Galvão, A. C. D. M., Da Silva, F. S., Silva, E. A. D. S., Palhano-Fontes, F., Maia-de-Oliveira, J. P., … & Galvão-Coelho, N. (2019). Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca: observation from a randomized controlled trial. Frontiers in psychology, 10, 1234., https://doi.org/10.3389/fpsyg.2019.01234
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Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers

June 3, 2019 / Depressive Disorders, LSD, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

BACKGROUND:

Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100-200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0-26 μg) on mood and behavior in healthy volunteers under double-blind conditions.

METHODS:

Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed.

RESULTS:

LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected.

CONCLUSIONS:

Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.

Bershad, A. K., Schepers, S. T., Bremmer, M. P., Lee, R., & de Wit, H. (2019). Acute subjective and behavioral effects of microdoses of LSD in healthy human volunteers. Biological Psychiatry., 10.1016/j.biopsych.2019.05.019
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